Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized by abnormal accumulation of the amyloid b-protein (Ab) in brain regions subserving memory and cognition. Emerging evidence suggests that defects in the proteolytic degradation of Ab may contribute to the pathogenesis of a substantial fraction of idiopathic AD cases, and it is possible that such defects might be detected in clinical samples, particularly the cerebrospinal fluid (CSF). This pilot project seeks to directly determine whether alterations in Ab degradation in CSF might constitute a reliable biomarker for AD. Preliminary results from a small number of samples suggests that Ab catabolism within the CSF of AD patients is significantly reduced relative to age-matched controls. This pilot grant seeks to compare the relative rates of Ab degradation (Aim 1) and the specific site(s) of A2 hydrolysis (Aim 2) in a larger number of CSF samples from AD cases and controls. Furthermore, we will begin to establish the identity of the A2-degrading protease(s) present in CSF through inhibitor profiling (Aim 3). These pilot studies will establish the merit of using CSF A2 catabolism as a biomarker for AD. If successful, the results obtained from this pilot study could be used as the basis for future funding proposals.